Single nucleotide polymorphisms (SNPs) in genes involved in thyroid hormone metabolism may affect thyroid hormone bioactivity. We investigated the occurrence and possible effects of SNPs in the deiodinases (D1–D3), the TSH receptor (TSHR), and the T₃ receptor β (TRβ) genes.

SNPs were identified in public databases or by sequencing of genomic DNA from 15 randomly selected subjects (30 alleles). Genotypes for the identified SNPs were determined in 156 healthy blood donors and related to plasma T₄, free T₄, T₃, rT₃, and TSH levels.

Eight SNPs of interest were identified, four of which had not yet been published. Three are located in the 3′-untranslated region: D1a-C/T (allele frequencies, C = 66%, T = 34%), D1b-A/G (A = 89.7%, G = 10.3%), and D3-T/G (T = 85.5%, G = 14.2%). Four are missense SNPs: D2-A/G (Thr92Ala, Thr = 61.2%, Ala = 38.8%), TSHRa-G/C (Asp36His, Asp = 99.4%, His = 0.6%), TSHRb-C/A (Pro52Thr, Pro = 94.2%, Thr = 5.8%), and TSHRc-C/G (Asp727Glu, Asp = 90.7%, Glu = 9.3%). One is a silent SNP: TRβ-T/C (T = 96.8%, C = 3.2%). D1a-T was associated in a dose-dependent manner with a higher plasma rT₃ [CC, 0.29 ± 0.01; CT, 0.32 ± 0.01; and TT, 0.34 ± 0.02 nmol/liter (mean ± se); P = 0.017], a higher plasma rT₃/T₄ (P = 0.01), and a lower T₃/rT₃ (P = 0.003) ratio. The D1b-G allele was associated with lower plasma rT₃/T₄ (P = 0.024) and with higher T₃/rT₃ (P = 0.08) ratios. TSHRc-G was associated with a lower plasma TSH (CC, 1.38 ± 0.07, vs. GC, 1.06 ± 0.14 mU/liter; P = 0.04), and with lower plasma TSH/free T₄ (P = 0.06), TSH/T₃ (P = 0.06), and TSH/T₄ (P = 0.08) ratios. No associations with TSH and iodothyronine levels were found for the other SNPs.

We have analyzed eight SNPs in five thyroid hormone pathway genes and found significant associations of three SNPs in two genes (D1, TSHR) with plasma TSH or iodothyronine levels in a normal population.